In the chemotherapy of tumors, particularly malignant tumors, in general, it is rare to achieve a desired antitumor effect by administration of a single antitumor agent, and in clinical situations, therefore, multiple drug therapy using two or more agents having different action mechanisms has been employed with the aim of increasing its effect. This combination therapy aims at alleviating side effects and enhancing antitumor action by combining antitumor agents having different action mechanisms, thereby to 1) decrease insensitive cell population, 2) prevent or delay development of drug resistance, 3) disperse toxicity by a combination of pharmaceutical agents with different toxicities and the like. However, random combinations of pharmaceutical agents with different action mechanisms for a combination therapy do not necessarily provide an antitumor effect-enhancing action or synergy.
It has been reported that histone deacetylase (HDAC) inhibitors induce high acetylation of histone and, as a result, induces transcription regulating activity on various genes, cell cycle inhibitory activity and apoptosis. Histone deacetylase inhibitors are also known as a potent anticancer agent (see JP-B-7-64872, Experimental Cell Research, US (1998), vol. 241, pp. 126-133).
For example, a compound represented by the formula (I)
or a pharmaceutically acceptable salt thereof (hereinafter to be also referred to as compound A), particularly a stereoisomer represented by the formula (II)
(hereinafter to be also referred to as FK228) or a pharmaceutically acceptable salt thereof are histone deacetylase inhibitors and reported to show a potent antitumor activity (see JP-B-7-64872 (corresponding to U.S. Pat. No. 4,977,138), Experimental Cell Research, US (1998), vol. 241, pp. 126-133).
However, a combined use of a histone deacetylase inhibitor and an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, such as cisplatin and the like, an antimetabolite antitumor agent such as 5-fluorouracil and the like or a taxane antitumor agent, all of which are conventionally widely used as antitumor agents, as well as an effect afforded by the combined use have not been reported yet.